Hydroxypropyl methyl cellulose phthalate, method for producing the same, and composition for hot-melt extrusion

ABSTRACT

There is provided a method for efficiently produce hydroxypropyl methyl cellulose phthalate (HPMCP) having excellent flowability, where acetic acid in a reaction product mixture subjected to a wash and recovery step can be reduced. More specifically, there is provided a method for producing HPMCP including an esterification step of esterifying hydroxypropyl methyl cellulose (HPMC) with phthalic anhydride in acetic acid as a solvent to obtain a reaction product solution containing HPMCP; a water addition step of adding water to the reaction product solution to obtain a water-added reaction product solution; an acetic acid removal step of removing at least a portion of the acetic acid from the water-added reaction product solution to obtain a mixture having an acetic acid content reduced; and a wash and recovery step of washing the mixture and recovering the HPMCP.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The invention relates to hydroxypropyl methyl cellulose phthalate, amethod for producing the hydroxypropyl methyl cellulose phthalate, and acomposition for hot-melt extrusion.

2. Related Art

Hydroxypropyl methyl cellulose phthalate (hereinafter also referred toas “HPMCP”) is a cellulose derivative having methoxy groups (—OCH₃),hydroxypropoxy groups (—OC₃H₆OH) and carboxybenzoyl groups(—COC₆H₄COOH), and is produced by chemically modifying a cellulose.

HPMCP is used as an enteric polymeric base material in a coatingapplication, or as a solid dispersion containing a poorly water-solubledrug, and thus widely used particularly in the pharmaceutical field.

Examples of the method for producing HPMCP include a method forproducing a carboxylate-containing cellulose derivative, comprising astep of esterifying a cellulose with a polyvalent carboxylic anhydridein acetic acid as a solvent in the presence of an alkali metalcarboxylate salt as a catalyst, while stirring by a biaxial stirrer,wherein an amount of the acetic acid as a solvent is 1 to 2 times theweight of the cellulose (JPH05-0339301A).

SUMMARY OF THE INVENTION

In a conventional method for producing HPMCP such as that inJPH5-339301A, water is added to a reaction product solution to obtain asuspension having HPMCP precipitated, and the HPMCP in the suspension iswashed with water to remove impurities. The suspension contains a largeamount of acetic acid used as a solvent during the esterification step.Acetic acid contained in the water used for washing is discardedtogether with the water because of difficulty in recovery. However, thej acetic acid is a factor of increasing the chemical oxygen demand (COD)of waste water. The acetic acid is also a factor of lowering the pH ofwaste water. The acetic acid is further a factor of odor.

Accordingly, after a suspension containing a large amount of acetic acidis subjected to a washing and recovering step, it is necessary tosubject the water used for washing to waste water treatment such asbiological treatment. An amount of acetic acid in the mixture subjectedto the washing and recovering step is desirably small to reduce the loadof the waste water treatment.

To reduce acetic acid in the mixture subjected to the washing andrecovering step, it is considered to reduce the amount of acetic acid tobe used in the esterification step. However, as described inJPH05-339301A, the reduction of the amount of acetic acid may make itdifficult to uniformly dissolve the cellulose in an acetic acid solventat a high concentration.

As described above, there is room for improvement in the conventionalmethod for producing HPMCP. There is also room for improvement offlowability of the conventional HPMCP with respect to a flowabilityproblem such as clogging in a hopper and a sanitary problem caused byHPMCP remaining inside the hopper and pipe.

As a result of extensive studies to solve the above problems, theinventors have found that removal of acetic acid from a reaction productsolution containing HPMCP can reduce acetic acid in a mixture subjectedto the wash and recovery step, and efficiently produce HPMCP havingexcellent flowability, and thus have completed the invention.

In one aspect of the invention, there is provided a method for producinghydroxypropyl methyl cellulose phthalate, the method comprising:

an esterification step of esterifying hydroxypropyl methyl cellulosewith phthalic anhydride in acetic acid as a solvent to obtain a reactionproduct solution containing hydroxypropyl methyl cellulose phthalate;

a water addition step of adding water to the reaction product solutionto obtain a water-added reaction product solution;

an acetic acid removal step of removing at least a portion of the aceticacid from the water-added reaction product solution to obtain a mixturehaving an acetic acid content reduced; and

a wash and recovery step of washing the mixture and recovering thehydroxypropyl methyl cellulose phthalate.

In another aspect of the invention, there is provided hydroxypropylmethyl cellulose phthalate having a volume fraction of sphericalparticles of 70.0% or more relative to all of hydroxypropyl methylcellulose phthalate particles, the all of hydroxypropyl methyl cellulosephthalate, being classified, on a basis of dynamic image analysis, intofine particles, the spherical particles and fibrous particles, wherein

the fine particles have a length of fiber of less than 40 μm;

the spherical particles have a length of fiber of 40 μm or more andconsist of first and second spherical particles, wherein the firstspherical particles have an elongation, which is a ratio of a diameterof fiber to a length of fiber, of 0.5 or more, and the second sphericalparticles have an elongation of less than 0.5, an aspect ratio, which isa ratio of a minimum Feret diameter to a maximum Feret diameter, of 0.5or more, and a circularity, which is a ratio of a perimeter (P_(EQPC))of a circle that has the same area as a projection area of a particle toa real perimeter (P_(real)) of a particle, of 0.7 or more;

the fibrous particles consist of long and short fibrous particles;

the long fibrous particles have a length of fiber of 200 μm or more andan elongation of less than 0.5, and consist of first and second longfibrous particles, wherein the first long fibrous particles have anaspect ratio of less than 0.5, and the second long fibrous particleshave an aspect ratio of 0.5 or more and a circularity of less than 0.7;and

the short fibrous particles have a length of fiber of 40 μm or more andless than 200 μm and an elongation of less than 0.5, and consist offirst and second short fibrous particles, wherein the first shortfibrous particles have an aspect ratio of less than 0.5, and the secondshort fibrous particles have an aspect ratio of 0.5 or more and acircularity of less than 0.7.

According to the invention, since at least a portion of acetic acid isremoved from the reaction product solution containing HPMCP, the amountof acetic acid in the mixture to be subjected to the wash and recoverstep can be reduced. For this reason, the burden in the waste watertreatment is expected to be reduced, and the cost can be reduced byreusing the removed acetic acid.

In addition, HPMCP having excellent flowability can be produced. Forthis reason, the mixing uniformity of HPMCP and a drug in thecomposition for hot-melt extrusion can be improved, and the bridgeformation by the mixed powder of HPMCP and a drug in a hopper can bereduced. The uniformity of the drug content, the improvement of the massratio of HPMCP to the drug, the quantitative supply and continuousoperation can be expected.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a flow chart of dividing “all particles” of HPMCP into fourtypes of particles: “fine particles”, “long fibrous particles (LF1 andLF2)”, “short fibrous particles (SF1 and SF2)” and “spherical particles(S1 and S2)”.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Regarding the method for producing HPMCP, there will be described anesterification step of esterifying hydroxypropyl methyl cellulose withphthalic anhydride in acetic acid as a solvent to obtain a reactionproduct solution containing HPMCP.

Hydroxypropyl methyl cellulose (hereinafter also referred to as “HPMC”)is a non-ionic water-soluble cellulose ether. HPMC synthesized by aknown method, or commercially available HPMC may be used.

The DS of methoxy groups of HPMC is preferably from 1.10 to 2.20, morepreferably from 1.30 to 2.10, still more preferably from 1.60 to 2.00,and particularly preferably from 1.80 to 2.00, from the viewpoint ofHPMC providing the reduced number of undissolved fibers. The MS ofhydroxypropoxy groups of HPMC is preferably from 0.10 to 1.00, morepreferably from 0.10 to 0.80, still more preferably from 0.15 to 0.60,and particularly preferably from 0.20 to 0.50, from the viewpoint ofHPMC providing the reduced number of undissolved fibers.

The DS of methoxy groups of HPMC represents the degree of substitutionof methoxy groups and means the average number of methoxy groups peranhydroglucose unit. The MS of the hydroxypropoxy groups of HPMCrepresents a molar substitution of hydroxypropoxy groups, and means theaverage mole number of hydroxypropoxy groups per mol of anhydroglucose.The DS of the methoxy groups and the MS of the hydroxypropoxy groups ofHPMC may be determined by conversion of the values obtained by themeasurement in accordance with the Japanese Pharmacopoeia SeventeenthEdition.

The viscosity at 20° C. of the 2% by mass aqueous solution of HPMC ispreferably from 1.0 to 30.0 mPa·s, more preferably from 2.0 to 20.0mPa·s, from the viewpoint of kneadability in the esterification step.The viscosity at 20° C. of a 2% by mass aqueous solution of HPMC may bemeasured by using a Ubbelohde viscometer in accordance with the methoddescribed in the monograph “Hypromellose” of the Japanese PharmacopoeiaSeventeenth Edition.

An amount of the acetic acid to be used is preferably from 3.5 to 10.0mol, more preferably from 4.5 to 7.0 mol, and still more preferably from5.0 to 6.5 mol, relative to 1 mol of HPMC, from the viewpoint ofdissolving HPMC and increasing the reaction rate.

An amount of the phthalic anhydride to be used is not particularlylimited as long as HPMCP having the desired substitution degree isobtained. It is preferably from 0.2 to 3.0 mol, more preferably from 0.4to 1.8 mol, relative to 1 mol of HPMC from the viewpoint of reactionefficiency.

The esterification reaction may be carried out in the presence of acatalyst. As the catalyst, an alkali metal carboxylate salt such assodium acetate is preferred from the viewpoint of economy. The optionalcatalyst may be used singly or in combination of two or more. Acommercially available catalyst may be used.

The amount of the optional catalyst to be used may be selected inconsideration of the substitution degree of HPMCP. It is preferably from0.1 to 3.0 mol, more preferably from 0.3 to 2.0 mol, relative to 1 molof HPMC from the viewpoint of reaction efficiency.

The esterification may be carried out in the presence of adepolymerization agent. As the depolymerization agent, an alkali metalchlorate such as sodium chlorate is preferable from the viewpoint ofeconomy. The optional depolymerization agent may be used singly or incombination of two or more. A commercially available depolymerizationmay be used.

The amount of the optional depolymerization agent to be used may beselected in consideration of the polymerization degree of HPMCP. It ispreferably from 0.01 to 0.20 mol, more preferably from 0.02 to 0.10 mol,relative to 1 mol of HPMC from the viewpoint of prevention of greatdecrease of the viscosity.

The esterification is preferably carried out using a kneader reactor orthe like from the viewpoint of reaction efficiency. The reactiontemperature in the esterification step is preferably from 60 to 120° C.,more preferably from 60 to 100° C., from the viewpoint of the reactionrate. The reaction time in the esterification step is preferably from 2to 8 hours, more preferably from 3 to 6 hours, from the viewpoint ofobtaining HPMCP having the desired substitution degrees.

Next, there is described a water addition step of adding water to thereaction product solution containing HPMCP to obtain a water-addedreaction product solution.

The water addition step allows unreacted phthalic anhydride to betreated.

The water is added in such an amount as not to precipitate the HPMCPfrom the viewpoint of preventing deterioration in transferability due toprecipitation of HPMCP. An amount of the water to be added is preferablynot more than 250 parts by mass, more preferably from 1 to 200 parts bymass, and still more preferably from 3 to 190 parts by mass, relative to100 parts by mass of the starting HPMC used in the esterificationreaction. The temperature of the reaction product solution containingHPMCP to be subjected to the addition of water is preferably from 60 to100° C. from the viewpoint of carrying out the acetic acid removal stepsequentially after adding the water.

Next, there will be described an acetic acid removal step of removing atleast a portion of acetic acid from the water-added reaction productsolution to obtain a mixture having the acetic acid content reduced.When sodium acetate is used as a catalyst, it is at the followingequilibrium, so that acetic acid derived from sodium acetate is notconsidered.

CH₃COONa+CH₃COOH═CH₃COOH+CH₃COONa

The method of removing at least a portion of acetic acid from thewater-added reaction product solution is not particularly limited. Theacetic acid removal step preferably comprises evaporating acetic acid byheating and stirring the water-added reaction product solution under areduced pressure to recover the acetic acid from the viewpoint ofefficiently removing and recovering acetic acid.

The acetic acid removal step may be carried out, for example, by usingan apparatus capable of stirring a high viscosity water-added reactionproduct solution and ensuring a sealed state for heating and reducedpressure or for reduced pressure. Examples of the apparatus include areactor being capable of heating and reducing an inside pressure andbeing equipped with a stirring blade that rotates; a reactor beingcapable of heating and reducing an inside pressure and being equippedwith a stirring blade that rotates and orbitally revolves. The apparatusis preferably a reactor capable of heating and reducing an insidepressure, and being equipped with a stirring blade that rotates andorbitally revolves, and for example, a 5 L vertical kneader reactor(Trimix TX-5 produced by INOUE MFG., Inc.) having three frame-shapedstirring blades that rotate and orbitally revolve. The peripheral speedin the rotational motion of one stirring blade is preferably from 0.01to 2.00 m/s from the viewpoint of uniformity of stirring in the aceticacid removal step. When the revolving motion is also used, theperipheral speed in the revolving motion of one stirring blade ispreferably from 0.001 to 2.00 m/s. As used herein, the term “peripheralspeed in the rotational motion” refers to the speed of the fastest part(i.e., the outermost periphery) of one stirring blade that rotates inthe apparatus used. The “peripheral speed in the revolving motion”refers to the speed of the fastest part (i.e., the outermost periphery)of one stirring blade that orbitally revolves in the apparatus used.

The acetic acid removal temperature in the acetic acid removal step ispreferably from 60 to 100° C. from the viewpoint of evaporation ofacetic acid. The reduced pressure in the acetic acid removing step ispreferably from −0.10 to −0.02 MPaG from the viewpoint of evaporation ofacetic acid. The reduced pressure in the acetic acid removal step can beperformed using an aspirator or the like.

The acetic acid removal time in the acetic acid removal step ispreferably from 0.1 to 5 hours from the viewpoint of productivity.

The evaporated acetic acid may be recovered in a cooled trap or the likeconnected to the apparatus. The trap is preferably cooled by ice or thelike. The recovered acetic acid may contain water.

The ratio of an amount of acetic acid removed in the acetic acid removalstep to an amount of acetic acid added as a solvent is referred to as aremoval percentage of acetic acid. The removal percentage of acetic acidis preferably 10.0% or more, more preferably from 20.0 to 95.0%, stillmore preferably from 40.0 to 90.0%, and particularly preferably from70.0 to 85.0%, from the viewpoint of flowability of HPMCP.

The removal percentage of acetic acid in the acetic acid removal step isdefined by the following formula considering that the removed aceticacid is a mixture of acetic acid and the water added in the wateraddition step.

Removal percentage (%) of acetic acid={(C×D/100)/A}×100

In the above formula, “A” means a mass ratio of acetic acid used as asolvent to a starting HPMC; “C” means a mass ratio of a recoveredmixture containing acetic acid to a starting HPMC; and “D” means aconcentration of acetic acid in the recovered mixture, wherein therecovered mixture also contains the water added in the water additionstep.

The mixture having the acetic acid content reduced and being subjectedto the wash and recovery step is preferably in a solid form from theviewpoint of flowability of HPMCP. When the mixture having the aceticacid content reduced is in a liquid form having high viscosity, a solidmixture may be obtained by cooling the mixture in a liquid form to roomtemperature.

An optional pulverization step of pulverizing the mixture in a solidform may be carried out between the acetic acid removal step and thelater-described wash and recovery step to obtain a pulverized mixturehaving the acetic acid content reduced from the viewpoint of efficientlywashing a mixture having the acetic acid content reduced in a solidform.

The pulverization may be carried out by using a pulverizer. Examples ofthe pulverizer include a high-speed rotary pulverizer such as a hammermill and a pin mill; a high shear apparatus such as a homogenizing mixerand a high shear mill; a roll-type pulverizer such as a roller mill; apulverizer with the grinding media such as a vibration mill and aplanetary mill; and a fluid-type pulverizer such as a jet mill.

When the mixture having the acetic acid content reduced is a solidhaving no stickiness, it may be pulverized as it is (i.e., drypulverization). When the mixture having the acetic acid content reducedis a sticky solid, the mixture may be subjected to addition of water andthen pulverized (i.e., wet pulverization). In general, when a mixturehaving the acetic acid content reduced is in a solid form, thestickiness becomes weaker as the removal percentage of acetic acidbecomes higher and the acetic acid content becomes smaller. Thetemperature of the water to be added is preferably from 5 to 40° C. fromthe viewpoint of pulverization of HPMCP. The amount of water to be addedis preferably from 100 to 1000 parts by mass relative to 100 parts bymass of the mixture in a solid form having the acetic acid contentreduced.

Next, there will be described a wash and recovery step of washing themixture having the acetic acid reduced and recovering the hydroxypropylmethyl cellulose phthalate.

The method of wash and recovery is not particularly limited. Examples ofthe method include a method comprising steps of mixing the mixturehaving the acetic acid content reduced with water to obtain awater-containing mixture, subjecting the water-containing mixture tocentrifugation, filtration, decantation or the like to obtain crudeHPMCP, dispersing the crude HPMCP in water for washing while stirringwith a stirrer to obtain a dispersion, and subjecting the dispersion tocentrifugation, filtration or the like to remove the water for washing;a method comprising a step of subjecting the mixture having the aceticacid content reduced or the crude HPMCP to continuous flow of water; anda method comprising a step of repeatedly replacing a portion of theliquid in the water-containing mixture by water.

The water-containing mixture containing the mixture having the aceticacid content reduced and water is preferably a suspension from theviewpoint of washing.

The temperature of the water to be used for washing is preferably from 5to 40° C. from the viewpoint of efficiently removing impuritiescontained in HPMCP. An amount of the water to be used for washing variesdepending on the washing method. For example, when crude HPMCP obtainedby centrifugation or filtration is washed, the amount of water to beused for washing is preferably 200 to 20000 parts by mass relative to100 parts by mass of the mixture having the acetic acid content reducedfrom the viewpoint of obtaining HPMCP with reduced impurities.

The amount of water to be used for washing may be preferably selected tofall within the above range in combination with the amount of wateradded in the water addition step.

The obtained HPMCP may be optionally dried. The drying temperature ispreferably from 40 to 100° C., more preferably from 40 to 80° C., fromthe viewpoint of preventing aggregation of HPMCP. The drying time ispreferably from 1 to 20 hours, more preferably from 3 to 15 hours, fromthe viewpoint of preventing aggregation of HPMCP.

The obtained HPMCP may be optionally subjected to sieving to obtain adesired average particle size.

The viscosity at 20° C. of a 10% by mass HPMCP solution obtained bydissolving HPMP in a mixed solvent of methanol and methylene chloride (amass ratio of methanol to methylene chloride of 1:1) is preferably from10.0 to 300.0 mPa·s, more preferably from 15.0 to 250.0 mPa·s and stillmore preferably from 15.0 to 220.0 mPa·s. The viscosity at 20° C. of a10% by mass HPMCP solution obtained by dissolving HPMCP in a mixedsolvent of methanol and methylene chloride (a mass ratio of methanol tomethylene chloride of 1:1) may be measured by using an Ubbelohdeviscometer in accordance with the method described in the monograph“Hypromellose Phthalate” of the Japanese Pharmacopoeia SeventeenthEdition.

The DS of the methoxy groups of HPMCP is preferably from 1.10 to 2.20,more preferably from 1.30 to 2.10, still more preferably from 1.60 to2.00, and most preferably from 1.80 to 2.00.

The MS of the hydroxypropoxy groups of HPMCP is preferably from 0.10 to1.00, more preferably from 0.10 to 0.80, still more preferably from 0.15to 0.60, and most preferably from 0.20 to 0.50.

The DS of the carboxy benzoyl groups of HPMCP is preferably from 0.10 to2.50, more preferably from 0.10 to 1.00, and still more preferably from0.40 to 0.80.

The DS of the methoxy groups, the DS of the carboxybenzoyl groups andthe MS of the hydroxypropoxy groups of HPMCP may be obtained byconversion of the values obtained in accordance with the method in themonographs “Hypromellose” and “Hypromellose Phthalate” of the JapanesePharmacopoeia Seventeenth Edition. The DS of the methoxy groups or thecarboxybenzoyl groups of HPMCP represents a degree of substitution, andmeans the average number of methoxy groups or carboxybenzoyl groups peranhydro glucose unit. Further, MS of the hydroxypropoxy groups of HPMCPrepresents a molar substitution, and means the average mole number ofhydroxypropoxy groups per anhydroglucose unit.

The particle size D₅₀ at the cumulative 50% in the particle sizedistribution of HPMCP may be appropriately selected depending on theapplication. It is preferably from 50 to 700 μm, more preferably from100 to 600 μm, and still more preferably from 300 to 500 μm from theviewpoint of the flowability of HPMCP.

The particle size ratio of D₉₀ to D₁₀, which is a ratio of the particlesize at cumulative 90% to the particle size at cumulative 10% in theparticle size distribution, is preferably 40.0 or less, more preferablyfrom 0.5 to 10.0, still more preferably from 1.0 to 4.0 and particularlypreferably from 1.0 to 3.5. The particle size ratio of D₉₀ to D₁₀represents the width of the particle size distribution.

The D₁₀, D₅₀ and D₉₀ in the particle size distribution of HPMCP may bemeasured at a dispersion pressure of 2 bars using a dry laserdiffraction particle size distribution analyzer (Mastersizer 3000produced by Malvern Panalytical Ltd.). The dry laser diffractionparticle size distribution analyzer is a device for jetting a powdersample with compressed air, irradiating it with a laser beam, andmeasuring the diameter of the volume-equivalent sphere by thediffraction intensity. Examples thereof include Mastersizer produced byBritish Malvern Panalytical Ltd. and a HELOS device produced by GermanSympatec GmbH.

The loose bulk density of HPMCP is preferably from 0.30 to 0.60 g/cm³,more preferably from 0.35 to 0.55 g/cm³, and still more preferably from0.40 to 0.53 g/cm³, from the viewpoint of handling. The loose bulkdensity means a bulk density in a loosely packed state. It is measuredby a method comprising steps of uniformly feeding a sample from 23 cmabove into a cylindrical container having a volume of 100 mL, a diameterof 5.03 cm and a height of 5.03 cm; then leveling the upper surface ofthe container; and weighing the container.

The flow rate of HPMCP in terms of flow through an orifice may bedetermined by the flow rate measurement, as described in GeneralInformation of the Japanese Pharmacopoeia Seventeenth Edition. The flowrate of HPMCP is preferably from 1.50 to 3.50 g/sec, more preferablyfrom 1.60 to 3.00 g/sec, from the viewpoint of handling. The flow rateextremely greatly depends on the measurement method used as described inGeneral Information of the Japanese Pharmacopoeia Seventeenth Edition.Thus, it is necessary to compare the flow rates measured under the sameconditions with each other. Details of the measurement conditions willbe described in Examples.

In this specification, HPMCP particles are divided into four types ofparticles: “long fibrous particles”, “short fibrous particles”,“spherical particles” and “fine particles”. FIG. 1 shows a flowchartsummarizing the method of dividing “all particles” of HPMCP into fourtypes of particles: “fine particles”, “long fibrous particles (LF1 andLF2)”, “short fibrous particles (SF1 and SF2)” and “spherical particles(S1 and S2)”.

A volume fraction of each type of HPMCP particles can be calculated bymeasuring the shape parameters such as a length of fiber (LEFI), adiameter of fiber (DIFI), an elongation, an aspect ratio and acircularity based on a dynamic-image analysis. The dynamic imageanalysis is a method in which images of particles dispersed in a fluidsuch as a gas or a solvent are continuously photographed and arebinarized and analyzed to obtain a particle diameter or a particleshape. The analysis may be performed by using, for example, adynamic-image analysis type particle diameter distribution analyzer,QICPIC/R16 (manufactured by Sympatec GmbH).

All particles A are divided into particles C having a length of fiber(LEFI) of 40 μm or more and fine particles B having a length of fiber ofless than 40 μm. The LEFI is defined as the length of the longest directpath that connects the ends of the particle within the contour of theparticle. A QICPIC/R16 equipped with an M7 lens has a detection limit of4.7 μm, and thus fails to detect a particle of an LEFI of less than 4.7μm. However, the volume of the particles having an LEFI of less than 4.7μm is extremely small relative to that of all particles of HPMCP, sothat it is negligible for the purposes of the invention.

The particles C having an LEFI of 40 μm or more are divided into firstspherical particles (S1) having an elongation of 0.5 or more andparticles D having an elongation of less than 0.5, wherein theelongation is a ratio (DIFI/LEFI) of a diameter of the fiber (DIFI) toLEF of the particle. The DIFI is defined as the minor diameter of aparticle, and is calculated by dividing the projection area of theparticle by the sum of all lengths of the fiber branches of theparticle.

The particles D having an LEFI of 40 μm or more and an elongation ofless than 0.5 are divided into particles E having an aspect ratio ofless than 0.5 and particles F having an aspect ratio of 0.5 or more,wherein the aspect ratio is a ratio (Fmin/Fmax) of the minimum Feretdiameter (Fmin) to the maximum Feret diameter (Fmax). Each particle hasan aspect ratio of more than 0 and not more than 1. The Feret diameteris the distance between two parallel tangent lines that put the particletherebetween. The maximum Feret diameter (Fmax) is the largest distancebetween pairs of tangent lines to the particle in consideration of allpossible orientations by changing the directions from 0° to 180°, andthe minimum Feret diameter (Fmin) is a minimum distance between pairs oftangent lines to the particle in consideration of all possibleorientations by changing the direction from 0° to 180°.

The fibrous particles E having an LEFI of 40 μm or more, and anelongation of less than 0.5, and an aspect ratio of less than 0.5 aredivided into first long fibrous particles (LF1) having an LEFI of 200 μmor more and first short fibrous particles (SF1) having an LEFI of lessthan 200 μm.

The particles F having an LEFI of 40 μm or more, and an elongation ofless than 0.5, and an aspect ratio of 0.5 or more are divided intosecond spherical particles (S2) having a circularity of 0.7 or more andfibrous particles G having a circularity of less than 0.7. Thecircularity is a ratio of the perimeter (P_(EQPC)) of a circle that hasthe same area as the projection area (A_(P)) of the particle to the realperimeter (P_(real)) of the particle, and is defined by the followingequation. Each particle has a circularity of more than 0 and not morethan 1. A particle having a smaller circularity has a more irregularshape. The EQPC is the diameter of a circle of an equal projection area,and is defined as the diameter of a circle that has the same area as theprojection area of the particle, and is also called Heywood diameter.

Circularity=P _(EQPC) /P _(real)=2√{square root over (π·A _(P))}/P_(real)

The fibrous particles G having an LEFI of 40 μm or more, an elongationof less than 0.5, an aspect ratio of 0.5 or more, and a circularity ofless than 0.7 are divided into second long fibrous particles (LF2)having an LEFI of 200 μm or more and second short fibrous particles(SF2) having an LEFI of less than 200 μm.

The volume (V_(m)) of the fine particles of HPMCP may be calculated bythe following equation where each fine particle is assumed to be asphere having a diameter of EQPC.

V _(m)=(π/6)×(EQPC)³ ×N _(m),

wherein N_(m) is the number of fine particles in a sample, and EQPC is amedian EQPC corresponding to the 50% cumulative value on a number-basedcumulative particle diameter distribution curve of fine particles.

In the specification, particles having an LEFI of 40 μm or more, whichare particles other than the fine particles having an LEFI of less than40 μm among all of the particles, are divided into “long fiberparticles”, “short fiber particles”, and “spherical particles”, whichare distinguished from each other. This division or classification isbased the above shape parameters of particles including LEFI, anelongation, an aspect ratio and a circularity.

<Long Fibrous Particles>

Particles satisfying the following definition of LF1 or LF2 are dividedinto “long fibrous particles”.

LF1: particles having an elongation of less than 0.5, an aspect ratio ofless than 0.5, and an LEFI (length of fiber) of 200 μm or more, and

LF2: particles having an elongation of less than 0.5, an aspect ratio of0.5 or more, a circularity of less than 0.7, and an LEFI (length offiber) of 200 μm or more.

The volume (V_(LF)) of the long fibrous particles of HPMCP may becalculated by the following equation wherein each long fibrous particleis assumed to be a cylindrical column having a bottom diameter of DIFIand a height of LEFI.

V _(LF)=(π/4)×(DIFI)²×(LEFI)×N _(LF),

wherein N_(LF) is the number of long fibrous particles in the sample,DIFI is a median DIFI corresponding to the 50% cumulative value on thenumber-based cumulative particle diameter distribution curve of longfibrous particles, and LEFI is a median LEFI corresponding to the 50%cumulative value on the number-based cumulative particle diameterdistribution curve of long fibrous particles.

The volume of particles satisfying the definition of LF1 and the volumeof particles satisfying the definition of LF2 are calculated inaccordance with the above equation, respectively, and a sum of thesevolumes means the volume of the long fibrous particles of HPMCP.

<Short Fibrous Particles>

Particles satisfying the following definition of SF1 or SF2 are dividedinto “short fibrous particles”.

SF1: particles having an elongation of less than 0.5, an aspect ratio ofless than 0.5, and an LEFI (length of fiber) of 40 μm or more and lessthan 200 μm, and

SF2: particles having an elongation of less than 0.5, an aspect ratio of0.5 or more, a circularity of less than 0.7, and an LEFI (length offiber) of 40 μm or more and less than 200 μm.

The volume (V_(SF)) of the short fibrous particles of HPMCP may becalculated by the following equation where each short fibrous particleis assumed to be a cylindrical column having a bottom diameter of DIFIand a height of LEFI, in the same manner as for the above long fibrousparticles.

V _(SF)=(π/4)×(DIFI)²×(LEFI)×N _(SF),

wherein N_(SF) is the number of short fibrous particles in the sample,DIFI is a median DIFI corresponding to the 50% cumulative value on thenumber-based cumulative particle diameter distribution curve of shortfibrous particles, and LEFI is a median LEFI corresponding to the 50%cumulative value on the number-based cumulative particle diameterdistribution curve of short fibrous particles.

The volume of particles satisfying the definition of SF1 and the volumeof particles satisfying the definition of SF2 are calculated inaccordance with the above equation, respectively, and a sum of thesevolumes means the volume of the short fibrous particles of HPMCP.

<Spherical Particles>

Particles satisfying the definition S1 or S2 is divided into “sphericalparticles”.

S1: particles having an elongation of 0.5 or more, and an LEFI (lengthof fiber) of 40 μm or more, and

S2: particles having an elongation of less than 0.5, an aspect ratio of0.5 or more, a circularity of 0.7 or more, and an LEFI (length of fiber)of 40 μm or more.

The volume (V_(S)) of the spherical particles of HPMCP may be calculatedby the following equation, wherein each spherical particle is assumed tobe a sphere having a diameter of EQPC.

V _(S)=(π/6)×(EQPC)³ ×N _(S),

where N_(S) is the number of spherical particles in the sample, and EQPCis a median EQPC corresponding to the 50% cumulative value on thenumber-based cumulative particle diameter distribution curve ofspherical particles.

The volume of the particles satisfying the definition S1 and the volumeof the particles satisfying the definition S2 are calculated inaccordance with the above equation, respectively, and a sum of thesevolumes means the volume of the spherical particles of HPMCP.

The volume fraction of each type of particles of HPMCP may be calculatedfrom the following corresponding equation on basis of the above definedvolumes, V_(m), V_(LF), V_(SF) and V_(S).

Volume fraction of fine particles={V _(m)/(V _(m) +V _(LF) +V _(SF) +V_(S))}×100

Volume fraction of long fibrous particles={V _(LF)/(V _(m) +V _(LF) +V_(SF) +V _(S))}×100

Volume fraction of short fibrous particles={V _(SF)/(V _(m) +V _(LF) +V_(SF) +V _(S))}×100

Volume fraction of spherical particles={V _(S)/(V _(m) +V _(LF) +V _(SF)+V _(S))}×100

The volume fraction of each type of particles, which are long fibrousparticles, short fibrous particles, spherical particles and fineparticles, is determined as follows. A dynamic image analysis typeparticle diameter distribution analyzer QICPIC/R16 (manufactured bySympatec GmbH) equipped with a quantitative feeder VIBRI/L, an air flowtype disperser RODOS/L and an M7 lens is used under the conditions of aframe rate of 500 Hz, an injector of 4 mm, a dispersion pressure of 1bar. The graphics of the imaged particles are analyzed by analysissoftware WINDOX5 Version 5.9.1.1 to determine the number-based medianEQPC, the number-based median LEFI, the number-based median DIFI, theelongation, the aspect ratio and the circularity with respect to eachtype of particles. The volume fraction of each type of particles iscalculated by the above equation based on the measured values. It isnoted that M7 is used as the division of analysis.

The volume fraction of the spherical particles of HPMCP is 70.0% ormore, preferably from 75.0 to 99.0%, and more preferably from 83.0 to97.0%, from the viewpoint of obtaining HPMCP excellent in flowability.

The volume fraction of the long fibrous particles of HPMCP is preferably30.0% or less, more preferably from 1.0 to 25.0%, and still morepreferably from 3.0 to 20.0%, from the viewpoint of flowability ofHPMCP.

The volume fraction of the short fibrous particles of HPMCP ispreferably 2.5% or less, more preferably from 0.0 to 1.5%, and stillmore preferably from 0.0 to 0.5%, from the viewpoint of flowability ofHPMCP.

The volume fraction of the fine particles of HPMCP is preferably 2.5% orless, more preferably from 0.0 to 1.5%, and still more preferably from0.0 to 0.5%, from the viewpoint of flowability of HPMCP.

Next, there will be described a composition for hot-melt extrusioncomprising the above-described hydroxypropyl methyl cellulose phthalateand a drug.

By using the above-described HPMCP having good flowability, the mixinguniformity of HPMCP and the drug in the composition for hot-meltextrusion, and formation of bridges in the hopper of the mixed powder ofHPMCP and the drug, can be improved. The uniformity of the drug content,the improvement of the mass ratio of HPMCP to the drug, the quantitativefeeding and the continuous operation can also be expected.

The drug is not particularly limited as long as it can be orallyadministered. Examples of the drug include a drug for the centralnervous system, a drug for the cardiovascular system, a drug for therespiratory system, a drug for the digestive system, an antibiotic, anantitussive and expectorant, an antihistamine, an antipyreticanti-inflammatory analgesic, a diuretic, an autonomic agent, anantimalarial agent, an antidiarrheal agent, a psychotropic, and vitaminsand derivatives thereof.

Examples of the drug for the central nervous system include diazepam,idebenone, naproxen, piroxicam, indomethacin, sulindac, lorazepam,nitrazepam, phenytoin, acetaminophen (another name: paracetamol),ethenzamide, and chlordiazepoxide.

Examples of the drug for the cardiovascular system include molsidomine,vinpocetine, propranolol, methyldopa, dipyridamole, furosemide,triamterene, nifedipine, atenolol, spironolactone, metoprolol, pindolol,captopril, isosorbide dinitrate, delapril hydrochloride, meclofenoxatehydrochloride, diltiazem hydrochloride, etileffine hydrochloride,digitoxin, and alprenolol hydrochloride.

Examples of the drug for the respiratory system include amlexanox,dextromethorphan, theophylline, pseudoephedrine, salbutamol, andguaifenesin.

Examples of the drug for the digestive system include a benzimidazoledrug having antiulcer action, such as2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylsulfinyl]benzimidazoleand5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]benzimidazole;cimetidine; ranitidine; pirenzepine hydrochloride; pancreatin;bisacodyl; and 5-aminosalicylic acid.

Examples of the antibiotic include talampicillin hydrochloride,bacampicillin hydrochloride, cefaclor, and erythromycin.

Examples of the antitussive and expectorant include noscapinehydrochloride, carbetapentane citrate, isoaminile citrate, anddimemorfan phosphate.

Examples of the antihistamine include chlorpheniramine maleate,diphenhydramine hydrochloride, and promethazine hydrochloride.

Examples of the antipyretic anti-inflammatory analgesic includeibuprofen, diclofenac sodium, flufenamic acid, sulpyrine, aspirin, andketoprofen.

Examples of the diuretic include caffeine.

Examples of the autonomic agent include dihydrocodeine phosphate,dl-methylephedrine hydrochloride, atropine sulfate, acetylcholinechloride, and neostigmine.

Examples of the antimalarial agent include quinine hydrochloride.

Examples of the antidiarrheal agent include loperamide hydrochloride.

Examples of the psychotropic include chlorpromazine.

Examples of the vitamins and derivatives thereof include vitamin A,vitamin B1, fursultiamine, vitamin B2, vitamin B6, vitamin B12, vitaminC, vitamin D, vitamin E, vitamin K, calcium pantothenate, and tranexamicacid.

Particularly using the HPMCP in accordance with the invention as acarrier of a solid dispersion containing a poorly water-soluble drug,solubility of the poorly water-soluble drug may be improved. Poorlywater-soluble drugs refer to drugs listed in the Japanese PharmacopoeiaSeventeenth Edition as “slightly soluble”, “very slightly soluble”, or“practically insoluble or insoluble” in water. The term “slightlysoluble” means that 1 g or 1 mL of a solid pharmaceutical productdissolves in 100 mL or more and less than 1000 mL of water within 30minutes when placed in a beaker and shaken vigorously at 20±5° C. for 30seconds every 5 minutes. The term “very slightly soluble” means that 1 gor 1 mL of a solid pharmaceutical product dissolves in 1000 mL or moreand less than 10,000 mL of water within 30 minutes in the same manner.The term “practically insoluble or insoluble” means that 1 g or 1 mL ofa solid pharmaceutical product dissolves in 10000 mL or more of waterwithin 30 minutes.

In the above test of pharmaceutical product, dissolution of a poorlywater-soluble drug means that the drug dissolves or becomes miscible inwater, and also means that fibers, etc. are found to be un-present orpresent at a very slight amount.

Examples of the poorly water-soluble drugs include azole-based compoundssuch as itraconazole, ketoconazole, fluconazole and methoconazole;dihydropyridine-based compounds such as nifedipine, nitrendipine,amlodipine, nicardipine, nilvadipine, ferrodipine and efonidipine;propionic acid-based compounds such as ibuprofen, ketoprofen andnaproxen; indoleacetic acid-based compounds such as indomethacin andacemetacin; griseofulvin; phenytoin; carbamazepine; and dipyridamole.

The mass ratio of HPMCAP to a drug is not particularly limited. It ispreferably from 1:0.1 to 1:10, more preferably from 1:0.2 to 1:5, fromthe viewpoint of storage stability in an amorphous state.

Further, the composition for hot-melt extrusion may comprise an optionaladditive such as a plasticizer and a surfactant for improvingmoldability during hot-melt extrusion, or the like.

Examples of the plasticizer include higher alcohols preferably having 10to 20 carbon atoms, such as cetyl alcohol and stearyl alcohol;polyhydric alcohols preferably having 2 to 6 valences, such as mannitol,sorbitol and glycerin; bead wax; triethyl citrate; polyalkylene glycolssuch as polyethylene glycol and polypropylene glycol; triacetin; dibutylsebacete; glycerin monostearate; and monoglycerin acetate.

The content of the plasticizer in the composition for hot-melt extrusionis preferably from 0.1 to 30% by mass from the viewpoint of storagestability.

Examples of the surfactant include an anionic surfactant such as sodiumlauryl sulfate; a nonionic surfactant such as diglycerides, poloxamers,polyoxyethylene sorbitan fatty acid esters (Twins 20, 60 and 80),glycerin fatty acid esters and propylene glycol fatty acid esters; and anatural surfactant such as lecithin and sodium taurocholate.

The content of the surfactant in the composition for hot-melt extrusionis preferably from 0.1 to 10% by mass from the viewpoint of storagestability.

The composition for hot-melt extrusion may be prepared by a methodcomprising a step of mixing HPMCP, a drug, an optional plasticizer andan optional surfactant to obtain a composition for hot-melt extrusion.The prepared composition for hot-melt extrusion may be introduced into ahot-melt extruder through a hopper, and extruded into a desired shapesuch as a circular shape, a square shape, a columnar shape or a film toobtain an extrudate.

The hot-melt extruder is not particularly limited as long as it is anextruder capable of melting and kneading HPMCP and a drug, while heatingand applying shear force with a piston or screw, and then extruding themfrom a die. It is preferably a twin-screw extruder to obtain a moreuniform extrudate. Specific examples include Capilograph (single-screwpiston type extruder) produced by Toyo Seild Seisaku-sho, Ltd.; NANO 16(twin-screw extruder) produced by Leistritz Extrusionstechnik GmbH; MiniLab (twin-screw extruder) and Pharma Lab (twin-screw extruder) producedby Thermo Fisher Scientific Inc.

The hot-melt temperature is not particularly limited. It is preferably atemperature at which the composition for hot-melt extrusion is meltedand reasonably extruded, while avoiding thermal decompositions of thedrug and HPMCP as much as possible. The hot-melt temperature ispreferably from 50 to 250° C., more preferably from 60 to 200° C., andstill more preferably from 90 to 190° C., in consideration of themelting points of the drug and HPMCP as well as the melting point of thecomposition for hot-melt extrusion.

The conditions for hot-melt extrusion may be appropriately selecteddepending on the properties of the composition for hot-melt extrusion inaccordance with a usual method.

The hot-melt extrudate after extrusion is cooled at the die outlet orlater by natural cooling or cold blowing at room temperature (from 1 to30° C.). The hot-melt extrudate is desirably cooled to 50° C. or less,more preferably 30° C. or less, in order to minimize thermaldecomposition of a drug and to suppress recrystallization of anamorphous drug.

The hot-melt extrudate after cooling may be optionally pelletized intopellets of from 0.1 to 5 mm by a cutter, or pulverized into granules orpowder for particle size adjustment. An impact mill such as a jet mill,a knife mill or a pin mill is preferably used for the pulverizationbecause it has a structure which hardly raises the product temperature.When the temperature in the cutter and the pulverizer becomes high,HPMCP is thermally softened and the particles are adhered to each other.Accordingly, pulverization is preferably carried out under cold airblowing.

EXAMPLES

Hereinafter, the invention will be described in detail with reference toExamples and Comparative Example. It should not be construed that theinvention is limited by or to them.

In the acetic acid removal step, the concentration of acetic acid in therecovered mixture containing at least the removed acetic acid and waterwas determined by liquid chromatography under the following conditions.

Equipment: Liquid Chromatograph LC-20AB produced by ShimadzuCorporation.

Column: ODS-3 (inside diameter of 4.6 mm, length of 15 cm, particle sizeof 5 μm, produced by GL Science Inc.)

Column temperature: 30° C., constant

Detector: Ultraviolet-visible absorption photometer (determined at 215nm, SPD-20AV produced by Shimadzu Corporation)

Mobile phase: A 0.02 mol/L aqueous solution of potassium dihydrogenphosphate, the solution being adjusted to pH 2.8 by addition ofphosphoric acid.

Flow rate: 1 mL/min

The measurement sample was prepared by subjecting the recovered mixturecontaining at least the removed acetic acid and water in the acetic acidremoval step to dilution with water by 500 times on a volume basis, andthen further to dilution with a mobile phase by 6.25 times on a volumebasis.

The flow rate of HPMCP in terms of flow through an orifice was measuredby a flowability tester BEP2 (Copley Scientific Ltd.) under thefollowing conditions to obtain an average value for two measurements.

Orifice size: 8 mm

Feed of HPMCP: 30 g

Standstill time: 30 seconds

Container: Cylindrical (diameter of 57 mm)

Example 1

The 600 g of HPMC having DS of methoxy groups of 1.88, MS ofhydroxypropoxy groups of 0.24 and a viscosity at 20° C. of 6.0 mPa·s asdetermined in a 2 mass % aqueous solution, 960.0 g of glacial aceticacid, 498.0 g of phthalic anhydride, 253.0 g of sodium acetate and 9.5 gof sodium chlorate were placed in a 5 L vertical kneader reactor (TrimixTX-5 produced by INOUE MFG., Ltd.) equipped with three frame-shapedstirring blades which rotate and orbitally revolve; and stirred at 85°C. for 4.5 hours to obtain 2320.5 g of a reaction product solutioncontaining HPMCP.

Next, the reaction product solution containing HPMCP was subjected toaddition of 27.0 g of water in the same reactor, while maintaining 85°C., and stirred to obtain 2347.5 g of a water-added reaction productsolution. The equivalent relationship in the esterification reaction isshown in Table 1.

TABLE 1 glacial phthalic sodium sodium acetic acid anhydride acetatechlorate HPMC (mol/mol (mol/mol (mol/mol (mol/mol (g) (mol) (g) HPMC)(g) HPMC) (g) HPMC) (g) HPMC) 600.0 3.0 960.0 5.4 498.0 1.1 253.0 1.09.5 0.03

Subsequently, the internal pressure in the same kneader reactor wasreduced to −0.09 MPaG by using an aspirator (A-1000S produced by TokyoRika-Kikai Co., Ltd.), and stirred at 85° C. for 30 minutes to recoveracetic acid into an ice-cooled trap. The recovered acetic acid containedwater, and the amount of the recovered mixture containing at leastacetic acid and water was 253.8 g. Then, by cooling the inside of thekneader reactor to room temperature, there was obtained a stickysolid-like mixture containing HPMCP and having the acetic acid contentreduced.

The peripheral speed in the rotational motion of each frame-shapedstirring blade in the esterification step, the water addition step andthe acetic acid removal step was 0.050 m/s, the peripheral speed in therevolving motion was 0.019 m/s. The ratio of the peripheral speed in therotational motion to the peripheral speed in the revolving motion was2.6. Further, the peripheral speeds in the rotational motion were thesame between all of the three frame-shaped stirring blades which rotatedand orbitally revolved.

Next, 100 parts by mass of the sticky solid-like mixture was subjectedto addition of 300 parts by mass of water of 20° C., and pulverized at arotational speed of 8000 rpm and a peripheral speed of 12.57 m/sec in ahomogenizing mixer (Homomixer MARK II 2.5 produced by PRIMIXCorporation; rotor diameter of 30.0 mm) to obtain a suspension of thepulverized mixture. Then, the pulverized mixture was filtered to obtaincrude HPMCP

Thereafter, a sequence of dispersing the crude HPMCP in water, stirringand filtering was repeated 10 times for washing to obtain washed HPMCPThe temperature of water used for washing was 20° C., and the amount ofwater used in each sequence for washing was 500 parts by mass relativeto 100 parts by mass of the solid-like mixture having the acetic acidcontent reduced. The washed HPMCP was dried for 2 hours at a temperatureof 80° C., and sieved through a sieve having an opening of 0.5 mm toobtain HPMCP.

Table 2 shows a mass ratio (A) of the glacial acetic acid used as asolvent to HPMC, a mass ratio (B) of water added in the water additionstep after completion of the esterification step to HPMC, a mass ratio(C) of a recovered mixture containing at least acetic acid and water inthe acetic acid removal step to HPMC, a concentration (D) of acetic acidin a recovered mixture containing at least acetic acid and water, aremoval percentage of acetic acid, and a form of the mixture having theacetic acid content reduced before subjected to the washing and recoverystep. Table 3 shows various properties of the obtained HPMCP.

Example 2

A non-sticky solid-like mixture containing HPMCP and having the aceticacid content reduced was obtained in the same manner as in Example 1except that the stirring time in the acetic acid removal step was 60minutes and an amount of the recovered mixture containing at least theremoved acetic acid and water was 775.0 g.

Next, the solid-like mixture having the acetic acid content reduced waspulverized at a rotational speed of 4000 rpm and a peripheral speed of55.79 m/s in Feather Mill FM-1F (produced by Hosokawa MicronCorporation; a rotor diameter of 266.4 mm) equipped with a knife-typemilling blade and a screen having an opening of 0.8 mm. Then, 100 partsby mass of the pulverized mixture having the acetic acid content reducedwas subjected to addition of 300 parts by mass of water of 20° C., andmixed to obtain the water-containing mixture of the pulverized mixtureand water. The water-containing mixture was filtered to obtain crudeHPMCP.

Thereafter, a sequence of dispersing the crude HPMCP in water, stirringand filtering was repeated 10 times for washing to obtain washed HPMCP.The temperature of water used for washing was 20° C., and the amount ofwater used in each sequence for washing was 500 parts by mass relativeto 100 parts by mass of the solid-like mixture having the acetic acidcontent reduced. Thereafter, the washed HPMCP was dried, and sieved inthe same manner as in Example 1 to obtain HPMCP. The results are shownin Tables 2 and 3.

Example 3

HPMCP was obtained in the same manner as in Example 1 except that anamount of water added to the reaction product solution containing HPMCPwas 1104.0 g, the stirring time in the acetic acid removal step was 60minutes, and an amount of the recovered mixture containing at leastacetic acid and water was 1230.2 g. It is noted that a sticky solid-likemixture containing HPMCP and having the acetic acid content reduced wasobtained in the acetic acid removal step. The results are shown inTables 2 and 3.

Example 4

HPMCP was obtained in the same manner as in Example 1 except that anamount of water added to the reaction product solution containing HPMCPwas 1104.0 g, the stirring time in the acetic acid removal step was 120minutes, and an amount of the recovered mixture containing at leastacetic acid and water was 1719.5 g. It is noted that a sticky solid-likemixture containing HPMCP and having the acetic acid content reduced wasobtained in the acetic acid removal step. The results are shown inTables 2 and 3.

Comparative Example 1

HPMCP was obtained in the same manner as in Example 1 except that anamount of water added to the reaction product solution containing HPMCPwas 1104.0 g, and the water-added reaction product solution was placedin a homogenized mixer in the absence of the acetic acid removal step.The results are shown in Tables 2 and 3.

TABLE 2 mass ratio (B) mass ratio (C) conc. (D) removal mass ratio (A)of water of recovered of acetic percentage form of of glacial added inmixture acid in of the mixture acetic acid water addition containingrecovered acetic having acetic as solvent step acetic acid mixture acidacid content to HPMC to HPMC to HPMC (mass %) (%) reduced Example1 1.600.05 0.42 95.2 25.2 solid Example2 1.60 0.05 1.29 98.6 79.2 solidExample3 1.60 1.84 2.05 41.9 53.7 solid Example4 1.60 1.84 2.87 44.179.0 solid Comp. Ex. 1 1.60 1.84 0.00 — — liquid

TABLE 3 particle size loose bulk flow viscosity D₅₀ ratio of densityrate (mPa · s) MeO HPO Cbz (μm) D₉₀ to D₁₀ (g/cm³) (g/sec) Example1 34.81.89 0.25 0.65 380 3.14 0.378 1.633 Example2 34.8 1.89 0.25 0.61 3732.73 0.489 2.770 Example3 34.8 1.87 0.24 0.61 413 3.33 0.455 1.743Example4 34.8 1.87 0.24 0.55 401 2.65 0.506 2.867 Comp. Ex. 1 34.8 1.890.25 0.67 416 3.87 0.179 1.132 long short spherical fibrous fibrous fineparticles particles particles particles (%) (%) (%) (%) Example1 80.719.1 0.1 0.1 Example2 94.0 5.9 0.1 0.0 Example3 83.0 16.9 0.1 0.0Example4 88.7 11.2 0.1 0.0 Comp. Ex. 1 27.6 69.7 2.1 0.6 *1 “viscosity”means the viscosity at 20° C. of a 10% by mass solution of HPMCP in amixed solvent of methanol and methylene chloride (mass ratio of 1:1),“MeO” means methoxy groups, “HPO” means hydroxypropoxy groups, and “Cbz”means carboxybenzoyl groups.

By carrying out the acetic acid removal step, there was obtained HPMCPhaving a volume fraction of spherical particles of 70.0% or more. A goodparticle size ratio of D₉₀ to D₁₀, a good loose bulk density, and a goodflow rate were exhibited. In addition, cost reduction can be expected byreducing the burden in wastewater treatment and reusing the recoveredacetic acid. Further, the mixing uniformity of HPMCP and a drug in thecomposition for hot-melt extrusion, and the formation of bridges in thehopper of the mixed powder of HPMCP and the drug can be improved.Uniformity of the drug content, the improvement of the mass ratio ofHPMCP to the drug, quantitative supply and continuous operation can beexpected.

1. A method for producing hydroxypropyl methyl cellulose phthalate comprising: an esterification step of esterifying hydroxypropyl methyl cellulose with phthalic anhydride in acetic acid as a solvent to obtain a reaction product solution containing hydroxypropyl methylcellulose phthalate; a water addition step of adding water to the reaction product solution to obtain a water-added reaction product solution; an acetic acid removal step of removing at least a portion of the acetic acid from the water-added reaction product solution to obtain a mixture having an acetic acid content reduced; and a wash and recovery step of washing the mixture and recovering the hydroxypropyl methyl cellulose phthalate.
 2. The method for producing hydroxypropyl methyl cellulose phthalate according to claim 1, wherein an amount of the acetic acid removed in the acetic acid removal step corresponds to 10.0% or more of the solvent acetic acid.
 3. The method for producing hydroxypropyl methyl cellulose phthalate according to claim 1, wherein the acetic acid removal step comprises evaporating the acetic acid by heating and stirring the water-added reaction product solution under a reduced pressure.
 4. Hydroxypropyl methyl cellulose phthalate having a volume fraction of spherical particles of 70.0% or more relative to all of hydroxypropyl methyl cellulose phthalate particles, the all of the hydroxypropyl methyl cellulose phthalate particles, being classified, on a basis of dynamic image analysis, into fine particles, spherical particles and fibrous particles; the fine particles have a length of fiber of less than 40 μm; the spherical particles have a length of 40 μm or more and consist of first and second spherical particles, wherein the first spherical particles have an elongation, which is a ratio of a diameter of fiber to a length of fiber, of 0.5 or more, and the second spherical particle have an elongation of less than 0.5, an aspect ratio, which is a ratio of a minimum Feret diameter to a maximum Feret diameter, of 0.5 or more, and a circularity, which is a ratio of a perimeter (P_(EQPC)) of a circle that has the same area as a projection area of a particle to a real perimeter (P_(real)) of a particle, of 0.7 or more; the fibrous particles consist of long and short fibrous particles; the long fibrous particles have a length of fiber of 200 μm or more and an elongation of less than 0.5, and consist of first and second long fibrous particles, wherein the first long fibrous particles have an aspect ratio of less than 0.5, and the second long fibrous particles have an aspect ratio of 0.5 or more and a circularity of less than 0.7; and the short fibrous particles have a length of fiber of 40 μm or more and less than 200 μm and an elongation of less than 0.5, and consist of first and second short fibrous particles, wherein the first short fibrous particles have an aspect ratio of less than 0.5, and the second short fibrous particles have an aspect ratio of 0.5 or more and a circularity of less than 0.7.
 5. The hydroxypropyl methyl cellulose phthalate according to claim 4, having a cumulative 50% particle size D₅₀ of 50 to 700 μm, and a ratio (D₉₀/D₁₀) of a cumulative 90% particle size D₉₀ to a cumulative 10% particle size D₁₀ of 40.0 or less in the particle size distribution of the hydroxypropyl methyl cellulose phthalate.
 6. A composition for hot-melt extrusion, the composition comprising: the hydroxypropyl methyl cellulose phthalate according to claim 4; and a drug.
 7. The method for producing hydroxypropyl methyl cellulose phthalate according to claim 2, wherein the acetic acid removal step comprises evaporating the acetic acid by heating and stirring the water-added reaction product solution under a reduced pressure.
 8. A composition for hot-melt extrusion, the composition comprising: the hydroxypropyl methyl cellulose phthalate according to claim 5; and a drug. 